This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Biological membranes play host to a large number of the proteins with vital physiological roles, including: pumps, channels, carriers, receptors, enzymes and energy transducers. A molecular-level interpretation of protein-lipid interactions is essential to understand the insertion, folding and function of these membrane proteins. Microscopic simulation, combined with advanced statistical mechanical techniques, can assist in uncovering some hidden microscopic mechanisms. We have had much success using PSC resources to date and have uncovered some exciting mechanisms of protein movement in lipid bilayers and membrane regulation of activity. We calculate spatially varying free energy profiles of titratable and aromatic protein side-chains, attached to model transmembrane segments, throughout the bilayer to determine the thermodynamics governing protein conformational changes. We are also quantifying bilayer perturbations induced by the presence of model transmembrane segments to understand how hydrophobic mismatch (a principle frequently summoned to explain protein insertion, folding, activity, aggregation and lipid micro-domain formation) drives protein stability and activity. We particularly wish to understand the function of an important class of membrane proteins known as ion channels which allow selective permeation of charged molecules across the membrane and are associated with many neurological and cardiovascular disorders. We are simulating membranes of different composition around the KcsA potassium channel to investigate experimentally observed changes in protein activity and to understand the roles of polyunsaturated lipids in regulating protein activity. The ability to explain the influence of the bilayer environment is necessary to bridge the gap between structure and function and which will aid the development of specific drugs.